This Program Project is organized to study the structure-function and modulation of cardiac Na channels and their participation in excitation of the heart. It is a more focused continuation of a long-standing research program in cell biology of muscle. It will include a project devoted to Na channel gating and its unique cardiac properties, a project to study Na channel permeation and selectivity, a project to determine mechanisms of drug interaction with the Na channel, a core for molecular biology, and a core for computer/electronics/mechanical services. It will employ physiological, pharmacologica1, biophysical, and molecular biological tools to develop a better understanding of ion channel structure-function and to integrate these insights into a progressively improving molecular structural model of the channels. This insight is important to define channels as drug targets and as participants in the pathophysiology of cardiac arrhythmias.